Small cyclic compounds are conformationally restricted and, as such, exhibit increased specificity and affinity in binding to other molecules, as compared to linear compounds of the same size. Further, small cyclic compounds are thought to be more stable in cells than linear compounds, and are likely to be small enough to avoid recognition by host immune system and to cross the plasma membrane of a cell (Schreiber, 2000 Science 287, 1964-1969; Scott et al., 2001 Chem. Biol. 8, 801-815). These features make small cyclic compounds very attractive drugs for the treatment of a variety of human conditions, including those caused by cancer, inflammation and infectious agents.
It follows from the above that there is a great need for new types of small cyclic compounds that are readily produced, and a great need for libraries, particularly cellular libraries, of new small cyclic compounds that can be screened to identify potent new drugs.
Current methods for making cyclic compounds, however, generally fail to meet these needs. For example, linear compounds may be cyclized in vitro (e.g., during or after chemical synthesis) by reacting the ends of the compound together to form a covalent bond therebetween. Such methods, however, are usually highly inefficient because the ends of a compound are sterically prevented from reacting. This problem is particularly exacerbated in cyclizing smaller compounds, where the ends of the compound have less choice of conformational space. Further, cyclic compounds made by cyclizing linear compounds can be difficult to purify from the linear compounds, and, as such, such methods sometimes require sophisticated purification procedures. Accordingly, despite their attractiveness as drugs, it is generally impossible to produce and purify small cyclic compounds (e.g., those less than about 600 Da) in any useful amount using synthetic chemistry.
Accordingly, there is a great need for new methods for making small cyclic compounds, as well as a great need for new small cyclic compound libraries that can be screened to identify a cyclic compound with a desired activity. The invention set forth herein meets these needs.